Nucleocytoplasmic trafficking of macromolecules is a highly specific and tightly regulated process that occurs exclusively through the nuclear pore complex (NPC). NPC is composed of approximately 30 proteins, termed nucleoporins, which play crucial roles in several biological processes. Although, chromosomal translocation involving some nucleoporins are observed in hematological malignancies, however, their role in solid tumors is not known. Therefore, to study the role of nucleoporins in melanoma tumor growth and metastasis, we developed an integrative genomics approach by combining The Cancer Genome Atlas (TCGA) melanoma sample dataset analyses with functional genomics approach of an in vivo RNA interference (RNAi) screening. This approach identified NUP205 as the only nucleoporin that is essential for tumor growth and metastasis of BRAF- and NRAS-mutant melanoma. Additional experiments revealed that NUP205 confers anoikis resistance and stimulates MAK kinase and WNT signaling pathways. Based on these results, we hypothesize that NUP205 by regulating MAP kinase and WNT signaling pathways drives melanoma tumor growth and metastasis. The overall objective is to determine the role and mechanism of NUP205 in tumor growth and metastasis and test if NUP205-driven pathway can be targeted to treat melanoma. In Aim 1, we will determine the in vivo role of NUP205 in melanoma tumor growth and metastasis. To this end, using in vivo mouse models of melanoma tumor growth and organ-specific and spontaneous mouse models of melanoma metastasis, we will determine the role of NUP205 in facilitating melanoma tumor growth and metastasis. In Aim 2, we will determine the mechanism of NUP205 action. Based on our results, we will test whether the ability of NUP205 to stimulate MAP kinase via Raf kinase inhibitory protein (RKIP) and/or WNT signaling pathway via heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is required for it to confer anoikis resistance and promote melanoma tumor growth and metastasis. In Aim 3, we will determine the utility of targeting NUP205 regulated pathway for melanoma therapy. First, we will test if pharmacological inhibition of NUP205 downstream effector HS2ST1 enzyme by small molecule inhibitors can block metastatic tumor growth in vivo. Additionally, because NUP205 protein stabilization can confer resistance to BRAFV600E inhibitor vemurafenib, therefore, we will determine if inhibition of its downstream effector HS2ST1 can restore sensitivity to vemurafenib and prevent emergence of drug resistance. Clinical significance of these results will be established by analyzing pre- and post- vemurafenib treatment melanoma patient samples for the expression of NUP205 and its downstream effectors. Collectively, we expect to uncover a novel NUP205-driven druggable genetic vulnerability pathway that can be targeted for treating metastatic and drug resistant melanoma.